This is a competitive renewal application for years 21-25 of Program Project Grant HL-44612, which provides support for a coordinated, multi-disciplinary investigation of molecular and cellular mechanisms important to the field of transfusion medicine. Our application reflects ongoing, close collaborative ties that have existed amongst the Project Leaders for more than a decade, and who remain committed to interrelated research projects centered around the biology of blood and vascular cells. In PROJECT 1, Peter Newman seeks to examine the cooperative interactions between platelet integrins and members of the ITAM-family of signaling proteins that regulate platelet activation and adhesion, with relevance for thrombosis and hemostasis, as well as platelet storage and transfusion therapy. In PROJECT 2, Hartmut Weiler will examine the influence of elements of the Protein C pathway on hematopoietic stem cell survival and homing, with implications for the growing field of cellular therapies. PROJECT 3. led by Demin Wang, seeks to define the role of specific B lymphocyte populations in the cellular immune response underlying heparin-induced thrombocytopenia - studies that may transform our ability to diagnose and manage this complex bleeding and clotting disorder. PROJECT 4, led by Debra Newman, proposes to examine platelet signal transduction pathways that differentially regulate platelet activation responses to adhesive ligands, with hopes of identifying novel therapeutic targets and strategies for controlling thrombus formation. In PROJECT 5, Robert Montgomery proposes to examine the ability of von Willebrand factor to direct and stabilize factor Vlll in a series of novel large- and small-animal gene therapy protocols. The Administrative Core will oversee and coordinate the day-to-day scientific and fiscal operation of the Program. The Shared Instrumentation Core will continue to provide centralized instrumentation and expertise for DNA sequence analysis, peptide synthesis, image analysis, histology, flow cytometry, BIAcore analysis, and monoclonal antibody production. The Transgenic/Knockout Mouse Core will assist with vector design, transgenic mouse production, multi-trait breeding, and animal husbandry. Taken together, the overall scientific synergy of ideas, reagents and expertise afforded by these multiple collaborations should enable this Program Project in Transfusion Medicine Research to advance our understanding of the biology of blood and vascular cells, and to apply findings made toward treating blood diseases and enhancing the effectiveness of modern- day transfusion therapy.